Amphetamine-sensitized animals show a marked increase in dopamine D2 high receptors occupied by endogenous dopamine, even in the absence of acute challenges
Amphetamine-sensitized animals show a marked increase in dopamine D2 high receptors occupied by endogenous dopamine, even in the absence of acute challenges
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DOI：
10.1002/syn.10139
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发表时间：
2002-12-15
期刊：
影响因子：
2.3
通讯作者：
Kapur, S
中科院分区：
文献类型：
--
作者：
Seeman, P;Tallerico, T;Kapur, S
虽然对安非他明敏感的动物会夸大一系列与多巴胺 D-2 相关的行为，但对多巴胺 D-2 受体的研究表明，多巴胺 D-2 受体密度要么没有变化，要么有所下降，尤其是在使用放射性雷氯必利进行测量时。我们假设 D-2 受体的减少实际上可能是“明显的”，并且这些受体可能仍然存在，但被内源性多巴胺非竞争性“占据”。对安非他明敏感的动物（及其生理盐水对照）在最后一次注射后 4 周进行检查。我们首先测量了[H-3]雷氯必利体内结合，并观察到致敏动物体内雷氯必利结合水平降低了29%，表明多巴胺D-2受体水平明显较低。为了评估其原因，我们检查了在存在和不存在鸟苷酰亚胺二磷酸的情况下通过[H-3]雷氯必利测量的受体密度（使用体外斯卡查德分析）。该鸟嘌呤核苷酸将 D-2 受体的多巴胺结合高亲和力状态转化为低亲和力状态，从而可以测量该位点的绝对密度。正如之前报道的，苯丙胺致敏动物的 D-2 受体数量在常规结合中减少了 31%（B-max 15.6 vs. 22.7 pmol/g）。然而，添加鸟苷酰亚胺二磷酸后，两组的 B-max 均等（B-max 25.9 vs. 25.6 pmol/g），显示致敏动物中额外增加了 10.3 pmol/g，但盐水对照组中仅为 2.9 pmol/g。 [H-3]雷氯必利对受体的解离常数没有变化。被多巴胺占据的高亲和力状态下的多巴胺 D-2 受体增加了近四倍，这可以解释为什么安非他明敏感的动物对多巴胺释放挑战或多巴胺激动剂表现出几乎一个数量级的反应，即使绝对受体数量不变并且“表观”受体数量减少。 (C) 2002 Wiley-Liss, Inc.
While a range of dopamine D-2-related behaviors are exaggerated in amphetamine-sensitized animals, studies of the dopamine D-2 receptor have reported either no change or a decrease in dopamine D-2 receptor density-especially when measured using radioraclopride. We hypothesized that a decrease in D-2 receptors may actually be "apparent" and that these receptors may still be present, but are noncompetitively "occupied" by endogenous dopamine. Animals sensitized to amphetamine (and their saline controls) were examined 4 weeks after their last injection. We first measured the [H-3]raclopride binding in vivo, and observed that sensitized animals showed a 29% lower level of raclopride binding in vivo, suggesting an apparently lower level of dopamine D-2 receptors. To assess the reason for this we examined the density of receptors (using Scatchard analysis in vitro) measured by [H-3]raclopride in the presence and absence of guanilylimidodiphosphate. This guanine nucleotide converts the dopamine-bound high-affinity state of D-2 receptors into low-affinity states, thereby making measurable the absolute density of the sites. As previously reported, the amphetaminesensitized animals showed a 31% lower number of D-2 receptors in conventional binding (B-max 15.6 vs. 22.7 pmol/g). However, with the addition of guanilylimidodiphosphate there was an equalization of both groups (B-max 25.9 vs. 25.6 pmol/g), revealing an additional 10.3 pmol/g in the sensitized animals, but only 2.9 pmol/g in saline controls. There were no changes in the dissociation constant of [H-3]raclopride for the receptors. The nearly four-fold increase of dopamine D-2 receptors in the high-affinity state occupied by dopamine may explain why amphetamine-sensitized animals show almost an order of magnitude greater response to dopamine-releasing challenges or dopamine agonists, even though the absolute receptor number is unchanged and the "apparent" receptor number is decreased. (C) 2002 Wiley-Liss, Inc.